Acute kidney injury (AKI) is a major renal disease that is associated with high mortality and prevalence. Recent work further indicates that AKI contributes to the development and progression of chronic kidney disease (CKD). However, the mechanism of AKI-CKD transition is largely unclear. Renal interstitial fibrosis is a key pathological event in maladaptive kidney repair following AKI and its progression to CKD. While interstitial fibrosis may involve various cell types in post-AKI kidneys, the tubular epithelium plays a critical role. It has been suggested that hyperactive signaling in injured or regenerating tubules may enhance the production and release of profibrotic factors that drive downstream events for renal fibrosis and AKI-CKD transition. But, it remains elusive how the profibrotic status of renal tubules is induced and maintained in post-AKI kidneys. Autophagy is a cellular process of cytoplasmic degradation that has recently been implicated in the development of renal fibrosis; however, the published data are controversial and the role of autophagy in post-AKI renal fibrosis is largely unknown. Our preliminary data show that tubular autophagy is induced along with renal interstitial fibrosis weeks after ischemia/reperfusion (IR) AKI. This is associated by the activation of hypoxia-inducible factor 1 (HIF-1), a potential regulator of autophagy and fibrosis. In cultured cells, hypoxia induces the secretion of profibrotic factors in an autophagy-dependent manner. In the model of unilateral ureteral obstruction, blockade of autophagy results in the suppression of renal fibrosis. Based on these observations, we hypothesize that: Autophagy is induced via HIF-1 in renal tubular cells of post-IR kidneys. Upon induction, autophagy leads to a secretory phenotype in these tubular cells for the production and secretion of profibrotic factors, which activate interstitial fibroblasts to promote renal fibrosis. To test this hypothesis, the application will determine the role of tubular autophagy in post-IR renal fibrosis, delineate the involvement of HIF-1 in autophagy activation, and identify the key profibrotic factors that are produced in renal tubules in an autophagy-dependent manner for interstitial fibroblast activation. By elucidating tubular autophagy in post-AKI renal fibrosis, this application may lead to an in-depth understanding of AKI-CKD transition and the discovery of new therapeutic strategies.